POS0471 INDUCED ANTIBODIES DIRECTED TO THE ANGIOTENSIN RECEPTOR TYPE 1 PROVOKE SKIN AND LUNG INFLAMMATION AND DERMAL FIBROSIS AND ACT SPECIES OVERARCHING
Authors: X. Yue, J. Yin, X. Wang, H. Heidecke, A. Hackel, H. Grasshoff, A. Müller, E. Kostenis, X. Yu, F. Petersen, G. Riemekasten
Journal: Annals of the Rheumatic Diseases (2022)

Background Antibodies directed to the angiotensin receptor type 1 (AT1R) were found to be increased in patients with SSc ad they predict mortality and SSc complications (1, 2). In vitro studies suggested an involvement in the pathogenesis of systemic sclerosis (SSc). Objectives Here, we aim to determine the contribution and functions of AT1R autoantibodies (Abs) in vivo and in vitro as well as their capacity to recognize AT1R from different species. Methods C57BL/6J mice were immunized with membrane-embedded human AT1R or empty membrane as control. Phenotypic properties of various organs were examined by immunohistochemistry, immunofluorescence, and TUNEL apoptosis assay. A monoclonal (m)AT1R Ab was generated based upon this mouse model by hybridoma technology and transferred into C57BL/6J mice. Mice deficient for CD4+ and CD8+ T cells, B cells and AT1Ra/b served as controls. In vitro, Abs responses towards AT1R were measured using rat cardiomyocytes, human epithelial cells, AT1R-transfected HEK293 cells and primary human monocytes. Results AT1R-immunized mice developed perivascular skin and lung inflammation, lymphocytic alveolitis, weak endothelial apoptosis and skin fibrosis, not present in controls or mice deficient for CD4+ T and B cells. The contribution of AT1R Abs to skin manifestations and interstitial lung disease was demonstrated by application of a mAT1R Ab, which induced skin and lung inflammation, not observed in the AT1Ra/b knockout mice. IgG from immunized mice containing AT1R Abs and/or the mAT1R Ab activated rat cardiomyocytes and human monocytes. Treatment of AT1R-transfected HEK293 cells with the mAT1R Ab enhanced AT1R signaling in the presence of the endogenous agonist Angiotensin II. Conclusion Our immunization strategy successfully induced AT1R Abs, contributing to inflammation and most likely to fibrosis via activation of AT1R. Therefore, AT1R Abs are valuable targets for future therapies in SSc and possibly other AT1R Ab-related diseases. References [1]Riemekasten, G. et al. Involvement of functional autoantibodies against vascular receptors in systemic sclerosis. Ann. Rheum. Dis. 70, 530–536 (2011). [2]Becker, M. O. et al. Vascular receptor autoantibodies in pulmonary arterial hypertension associated with systemic sclerosis. Am. J. Respir. Crit. Care Med. 190, 808–817 (2014). Figure 1. AT1R immunization and induction of AT1R Abs in C57BL/6J mice induced lymphocytic alveolitis in bronchoalveolar fluid (A), interstitial lung disease (B) with increased inflammatory score (C) Figure 2. AT1R immunization and induction of AT1R Abs in C57BL/6J mice induced skin fibroses (A) as determined by collagen content (B) and skin thickness (C). Acknowledgements This manuscript was founded by the German Research Council RI1056/11-1-3 and the Excellence Cluster Precision Medicine in Inflammation and by the BMBF-founded Mesinflame project. Disclosure of Interests None declared.